A virus is a small parasite consisting of nucleic acid (RNA or DNA) enclosed in a protein coat. Viruses can only replicate by infecting a susceptible host cell and directing the host cell machinery to produce more viruses. Glycoproteins (located in the protein coat) mediate the adsorption to, and the penetration of, the virus into susceptible host cells.
Most viruses are classified into broad categories based on the types of nucleic acids formed during replication and the pathway by which mRNA is produced. In general, viruses have either RNA or DNA as their genetic material, wherein the nucleic acid can be single- or double-stranded.
Important virus families of the DNA type (also classified as Classes I and II viruses—See Harvey, L. et al., Molecular Cell Biology, Fourth Edition, W.H. Freeman and Company (2000)) include adenoviridae, herpesviridae, poxviridae, papovaviridae, densovirinae, and parvovirinae. Virus families typically classified of the RNA type (also classified as Classes III-VI, See Molecular Cell Biology) include birnaviridae, reoviridae, astoviridae, arterivirus, caliciviridae, coronaviridae, flaviviridae, picornaviridae, togaviridae, polioviruses, bornaviridae, filoviridae, paramyxovirinae, pneumovirinae, rhabdoviridae, bunyaviridae, and orthomyxoviridae.
Influenza, commonly known as the “flu,” is a contagious disease that is caused by the influenza virus, classified in the orthomyxoviridae family. There are three known influenza-type viruses which affect human beings: Influenza A, B and C. Influenza A viruses have been isolated from many animal species in addition to humans, while the influenza B and C viruses have been found to infect mainly humans.
Influenza viruses are enveloped viruses containing negative single-stranded RNA's which are segmented and encapsidated. The influenza virus envelope is characterized by the presence of two surface glycoproteins: hemagglutinin and neuraminidase. The influenza A and B virions are pleomorphic and are usually 80-120 nm in diameter. The influenza C virion has many distinctive properties and is thus distinguished from the closely related A and B virions.
Influenza viruses attack the respiratory tract in humans (i.e., nose, throat, and lungs). For example, infection with influenza A or B often can cause a highly contagious, acute respiratory illness. Influenza infection usually includes the following symptoms: fever, headache, tiredness (can be extreme), dry cough, sore throat, nasal congestion, and body aches.
It is estimated that millions of people in the United States—about 10% to 20% of U.S. residents—get influenza each year. The majority of this population generally recovers in one to two weeks. In some cases, however, complications can arise from an influenza infection. Those persons at highest risk for contracting complications from the flu include: persons over 50 years of age, children aged 6 to 23 months, women more than 3 months pregnant, persons living in a long-term care facility or institution, persons with chronic heart, lung, or kidney conditions, diabetes, or weakened immune system. Pneumonia, bronchitis, encephalitis, otitis media, rhinitis, and sinusitis are only a few examples of complications that result from an influenza infection. Moreover, the flu can make chronic health problems worse. For example, people with asthma may experience asthma attacks while they have the flu, and people with chronic congestive heart failure may have worsening of this condition that is triggered by the flu.
An average of about 36,000 people per year in the United States die from influenza, and 114,000 per year have to be admitted to the hospital as a result of the infection. Thus, influenza viruses have a major impact on morbidity leading to increases in hospitalization and in visits to health care providers. For example, high rates of hospitalization are often observed for subjects over 65 years of age and also for children less than 5 years of age.
Furthermore, the spread of influenza virus through a population can result in epidemics, which have considerable economic impact. High rates of mortality were observed due to influenza infection during the influenza epidemics of 1957, 1968 and 1977 (Fields Virology, Second Edition, Volume 1, pp. 1075-1152 (1990)). Periodically, the influenza virus causes a worldwide epidemic. For example, the influenza pandemic of 1918 reportedly caused about 20 million deaths worldwide and about 500,000 deaths in the United States (Medical Microbiology, Fourth Edition, University of Texas Medical Branch at Galveston (1996)).
Influenza viruses are predominantly transmitted from person to person via respiratory droplets (also known as droplet spread) that are released when coughing and/or sneezing. The influenza virus can remain suspended in the air in respiratory droplets for as long as 3 hours; but are sensitive to heat and are rapidly inactivated at temperatures above 50° C. The virus can survive for 24-48 hours on hard, non-porous surfaces (i.e., telephone receivers, computer keyboard, doorknob, kitchen countertop, toys); 8 hours on cloth, paper and tissue; and five minutes on hands (see Muir, P, “Treatment of Influenza. Essential CPE. Continuing Education from the Pharmaceutical Society of Australia,” Paragon Printers, Australasia, ACT (2002)). Typical methods of transmittal include mucous membrane contact with infected airborne respiratory droplets, person-to-person contact, contact with contaminated items (i.e., tissues soiled by infected nose and throat discharges).
Transmittal of influenza virus via respiratory droplets can occur as early as one day before a person experiences influenza-related symptoms. Adults can continue to transmit the virus to others for another three to seven days after the initial appearance of symptoms. Unlike adults, children have the ability to transmit the virus for longer than seven days. Symptoms are generally presented one to four days after the virus enters the body. In certain cases, a person can be infected with the flu virus but demonstrate no symptoms. During this time, those persons can still transmit the virus to others.
Few methods are available for preventing an influenza infection and a cure has yet to be developed. Methods for preventing an influenza infection include vaccination and antiviral medications. Three antiviral drugs (amantadine, rimantadine, and oseltamivir) have been approved in the United States and are commercially available for use in preventing or treating influenza virus disease. These compounds, however, are most effective when used prophylactically, which may allow influenza viruses to develop resistance to both compounds rapidly. See U.S. Pat. Nos. 3,352,912 and 3,152,180. Other compounds reported to have activity against influenza viruses have been disclosed in U.S. Pat. Nos. 6,271,373; 5,935,957; 5,821,243; 5,684,024; 3,592,934; 3,538,160; 3,534,084; 3,496,228; and 3,483,254.
There is a great need for new therapies for the treatment of viral diseases. Whereas there has been great progress in developing a variety of therapies for the treatment of bacterial infections, there are few viable therapies for the treatment of viruses. As described above, antiviral drugs and vaccines are primary methods used in the prevention and/or treatment of influenza infections. Ganciclovir, acyclovir and foscarnet are currently utilized for the treatment of herpes virus infections. However, these therapies can have substantial side effects based on their deleterious effects on host cell DNA replication or their effect on a limited number of viral infections. In addition, as noted above, viruses are known to develop resistance to therapies, which causes a progressive decline in efficacy.
Insofar as is known, cysteamine compounds have not been previously reported as being useful for the treatment of viral infections.